Voriconazole is a second-generation triazole medication having a methyl group added to Fluconazole derivative, and provides fungicidal activity against Aspergillus infections or other filamentous fungal infections and a wide spectrum of anti-fungal activity. It is known that Voriconazole has a higher effect of treating invasive Aspergillus infections as compared to the existing Amphotericin, provides an excellent effect of treating infections caused by yeast fungi, and shows a stronger activity against fungal enzymes as compared to mammal enzymes by a factor of 250. In addition, Voriconazole has a higher binding ability to the demethylation step of 14-ranosterol in filamentous fungi than the corresponding binding ability in yeast fungi. Therefore, it shows fungicidal activity against some filamentous fungi but shows cytostatic activity against yeast fungi.
Voriconazole has an effect 60-100 times higher than Fluconazole against all Candida species including Fluconazole-resistant fungi. In the case of Aspergillus, Voriconazole is effective to all species including Aspergillus terreus that is resistant against Amphotericin. Referring to the structure of Voriconazole, it specifically has two adjacent asymmetric carbon atoms. Organic synthetic processes for producing such asymmetric carbon skeletons are limited significantly and have several problems in their industrial application. Moreover, known processes produce four types of stereoisomers during the synthesis due to the presence of the two asymmetric carbon atoms, resulting in a drop in yield during the separation of such isomers. Therefore, it is necessary to increase the stereoselectivity of the reaction in which the two asymmetric carbon atoms are formed and to realize effective separation of a desired stereoisomer in order to prepare Voriconazole more effectively.
In the synthesis of Voriconazole, it is thought that two important steps are step i) of preparing the pyrimidine derivative as an intermediate for use in the subsequent coupling reaction with high yield and high purity, and step ii) of increasing stereoselectivity in carrying out the coupling reaction between the pyrimidine derivative and the ketone derivative to obtain the resultant tertiary alcohol with high purity and high yield.
First, the pyrimidine derivative has been prepared as depicted in the following Reaction Scheme 1 under reflux without any solvent according to Korean Patent No. 1993-0011039 and EP 0440372. It is reported that the yield of pyrimidine derivative is as low as 66%. However, the method of Reaction Scheme 1 is not suitable for mass production owing to its severe reaction condition and low yield.
In addition, Korean Patent No. 10-0269048 and EP 0871625 disclose that the pyrimidine derivative is prepared via the method of Reaction Scheme 1 in the presence of a solvent, and the yield of the target product is 90%. However, in this case, there are problems in that phosphoryl chloride used in an excessive amount is hardly removed and the resultant product has low purity.

Meanwhile, Korean Unexamined Patent Publication No. 10-2009-0014468 discloses a process for preparing substituted thiopyrimidine derivatives by introducing a thiol group to a pyrimidine derivative, as shown in the following Reaction Scheme 2, to increase the purity of the pyrimidine derivative.

However, the above process is not amenable to industrial mass production due to the increased number of steps as compared to Reaction Scheme 1, the use of expensive thiol derivatives, and the bad odor generated during the step using thiol.
Next, Korean Patent No. 1993-0011039 and EP 0440372 disclose processes for carrying out a coupling reaction between pyrimidine derivatives and ketone derivatives. Herein, as shown in the following Reaction Scheme 3, LDA (lithium diisopropylamide), a strong base, or sodium bis(trimethylsilyl)amide is used to perform the coupling reaction.

However, the above methods are problematic in that they use highly explosive strong bases and require equipment capable of cryogenic reaction. Above all, the methods provide very low yield due to the low stereoselectivity and difficulty in separating isomers, and thus are not amenable to mass production.
To overcome the above-mentioned problems, Korean Patent No. 10-0269048 and EP 0871625 disclose a method by which the stereoselectivity is increased through the Reformatsky-type coupling reaction as depicted in the following Reaction Scheme 4, and enantiomeric pairs (2R,3S/2S,3R) are separated in the form of their hydrochloride salts via crystallization, thereby increasing the yield.

However, the method is problematic in that it results in a relatively low yield of 65% despite a high ratio of the enantiomeric pairs of 9:1 (2R,3S/2S,3R:2R,3R/2S,3S). The method has another problem related to the removal of halo after the hydrochloride salts are treated with base.
EP 0069442 discloses a method for preparing 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone, one of the main intermediates of Voriconazole, according to the following Reaction Scheme 5.

However, the above method provides a low yield of 40%. Under these circumstances, the present inventors have conducted intensive studies to develop a process for preparing Voriconazole, which includes forming a novel pyrimidine derivative as an intermediate with high purity and high yield, carrying out the Reformatsky-type coupling reaction between the intermediate and ketone derivative to increase the stereoselectivity, and carrying out crystallization to obtain Voriconazole with high purity and high yield in a large scale. The process for preparing Voriconazole using the novel intermediate is highly economical and efficient, and provides high yield and high purity.